Imidazole derivatives

ABSTRACT

The invention relates to imidazole derivatives which have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. 
     The invention also relates to a pharmaceutically-suitable acid-addition salt of the above compound. 
     The invention further relates to a composition comprising an imidazole derivative as described above, or a pharmaceutically-suitable acid-addition salt thereof, and to processes for preparing such compounds.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.11/950,449, filed Dec. 5, 2007, now pending; which claims the benefit ofEuropean Patent Application No. 06126307.5, filed Dec. 18, 2006. Theentire contents of the above-identified applications are herebyincorporated by reference.

FIELD OF THE INVENTION

This invention relates to compounds which have a good affinity to thetrace amine associated receptors (TAARs), especially for TAAR1.

These compounds are useful in the treatment or prevention of, interalia, disorders of the central nervous system, for example, thetreatment or prevention of depression, psychosis, Parkinson's disease,anxiety and/or attention deficit hyperactivity disorder (ADHD).

The invention relates also to processes for preparing such compounds anda pharmaceutical composition comprising such a compound.

BACKGROUND OF THE INVENTION

The classical biogenic amines (serotonin, norepinephrine, epinephrine,dopamine, histamine) play important roles as neurotransmitters in thecentral and peripheral nervous system. Deutch, A. Y. and Roth R. H.(1990) Neurotransmitters. In Fundamental Neuroscience (2nd ed.)(Zigmond, M. J., Bloom, F. E., Landis, S. C., Roberts, J. L., and SquireL. R., eds.) 193-234, Academic Press. Their synthesis and storage, aswell as their degradation and reuptake after release are tightlyregulated. An imbalance in the levels of biogenic amines is known to beresponsible for the altered brain function under many pathologicalconditions. Wong, M. L. and Licinio, J. (2001) Nat. Rev. Neurosci. 2,343-351; Carlsson, A. et al. (2001), Annu. Rev. Pharmacol. Toxicol. 41,237-260; Tuite, P. and Riss, J. (2003), Expert Opin. Investig. Drugs 12,1335-1352; Castellanos, F. X. and Tannock, R. (2002), Nat. Rev.Neurosci. 3, 617-628.

A second class of endogenous amine compounds, the so-called trace amines(TAs) significantly overlap with the classical biogenic amines regardingstructure, metabolism and subcellular localization. The TAs includep-tyramine, β-phenylethylamine, tryptamine and octopamine, and they arepresent in the mammalian nervous system at generally lower levels thanclassical biogenic amines. Usdin, E. and Sandler, M. eds. (1984), TraceAmines and the brain, Dekker. Their disregulation has been linked tovarious psychiatric diseases like schizophrenia and depression and forother conditions like attention deficit hyperactivity disorder, migraineheadache, Parkinson's disease, substance abuse and eating disorders.Lindemann, L. and Hoener, M. (2005), Trends in Pharmacol. Sci. 26,274-281; Branchek, T. A. and Blackburn, T. P. (2003), Curr. Opin.Pharmacol. 3, 90-97; Premont, R. T. et al. (2001), Proc. Natl. Acad.Sci. U.S.A. 98, 9474-9475.

For a long time, TA-specific receptors had only been hypothesized basedon anatomically discrete high-affinity TA binding sites in the centralnervous system of humans and other mammals. Mousseau, D. D. andButterworth, R. F. (1995), Prog. Brain Res. 106, 285-291; McCormack, J.K. et al. (1986), J. Neurosci. 6, 94-101. Accordingly, thepharmacological effects of TAs were believed to be mediated through thewell known machinery of classical biogenic amines, by either triggeringtheir release, inhibiting their reuptake or by “crossreacting” withtheir receptor systems. Premont, R. T. et al. (2001), Proc. Natl. Acad.Sci. U.S.A. 98, 9474-9475; Dyck, L. E. (1989), Life Sci. 44, 1149-1156;Parker, E. M. and Cubeddu, L. X. (1988), J. Pharmacol. Exp. Ther. 245,199-210. This view changed significantly with the recent identificationof several members of a novel family of GPCRs, the trace amineassociated receptors (TAARs). Lindemann, L. and Hoener, M. (2005),Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005),Genomics 85, 372-385.

There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genesin mouse (including 1 pseudogene). The TAAR genes do not contain introns(with one exception, TAAR2 contains 1 intron) and are located next toeach other on the same chromosomal segment. The phylogeneticrelationship of the receptor genes, in agreement with an in-depth GPCRpharmacophore similarity comparison and pharmacological data suggestthat these receptors form three distinct subfamilies. Lindemann, L. andHoener, M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L.et al. (2005), Genomics 85, 372-385. TAAR1 is in the first subclass offour genes (TAAR1-4) highly conserved between human and rodents. TAsactivate TAAR1 via Gαs. Disregulation of TAs was shown to contribute tothe aetiology of various diseases like depression, psychosis, attentiondeficit hyperactivity disorder, substance abuse, Parkinson's disease,migraine headache, eating disorders, metabolic disorders and thereforeTAAR1 ligands have a high potential for the treatment of these diseases.

It has been found that the compounds of formula I (described below) havea good affinity to the TAARs, especially for TAAR1.

The compounds as useful in the treatment or prevention of depression,anxiety disorders, bipolar disorder, attention deficit hyperactivitydisorder (ADHD), stress-related disorders, psychotic disorders such asschizophrenia, neurological diseases such as Parkinson's disease,neurodegenerative disorders such as Alzheimer's disease, epilepsy,migraine, hypertension, substance abuse and metabolic disorders such aseating disorders, diabetes, diabetic complications, obesity,dyslipidemia, disorders of energy consumption and assimilation,disorders and malfunction of body temperature homeostasis, disorders ofsleep and circadian rhythm, and/or cardiovascular disorders. Preferably,the compounds are useful in the treatment or prevention of disorders ofthe central nervous system, for example, the treatment or prevention ofdepression, psychosis, Parkinson's disease, anxiety and/or attentiondeficit hyperactivity disorder (ADHD).

SUMMARY OF THE INVENTION

The present invention is directed to a compound according to formula I,

whereinR is selected from the group consisting of hydrogen, lower alkyl andamino;X is selected from the group consisting of —CH₂—, —CH(lower alkoxy)-,—CH(OH)—, and —NH—;Y is selected from the group consisting of —CH₂, —CH(lower alkyl)-,—CH(lower alkoxy)-, —O—, —S—, —S(O)—, —S(O)₂—, —CH(phenyl)- and —C(loweralkyl)₂-; andAr is selected from the group consisting of phenyl, napthtyl andbenzofuranyl, said phenyl, mapthyl, or benzofuranyl being unsubstitutedor substituted by one or more substituents, each substituent beingindependently selected from the group consisting of lower alkyl, loweralkyl substituted by halogen, halogen, lower alkoxy, lower alkoxysubstituted by halogen, hydroxy, amino, di-alkylamino, morpholinyl,phenyl, benzyl and O-benzyl;with the provisio that, wherein, when X is —NH—, Y is selected from thegroup consisting of —CH₂, —CH(lower alkyl)-, —CH(lower alkoxy)-,—CH(phenyl)- or —C(lower alkyl)₂-; and the further proviso that saidcompound is not

-   5-phenethyl-1H-imidazole,-   5-(2-phenyl-propyl)-1H-imidazole,-   1-(1H-imidazol-4-yl)-2-phenyl-ethanol,-   5-(2,2-diphenyl-ethyl)-1H-imidazole,-   4-(2-m-tolyl-ethyl)-1H-imidazole,-   4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole,-   4-(biphenyl-2-yloxymethyl)-1H-imidazole,-   5-(2-methyl-2-phenyl-propyl)-1H-imidazole,-   4-(2-chloro-phenoxymethyl)-1H-imidazole,-   4-(2-fluoro-phenoxymethyl)-1H-imidazole,-   4-o-tolyloxymethyl-1H-imidazole,-   4-(3-chloro-phenoxymethyl)-1H-imidazole,-   4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or-   5-methyl-4-phenylsulfanylmethyl-1H-imidazole.

The present invention also relates to a pharmaceutically-suitableacid-addition salt of such a compound.

The invention includes all racemic mixtures, all their correspondingenantiomers and/or optical isomers.

In addition, all tautomeric forms of compounds of formula I are alsoencompassed by the present invention.

The present invention is also directed to processes for the preparationof the above compound.

The present invention is also directed to a pharmaceutical compositioncomprising the above compound or a pharmaceutically-suitableacid-addition salt thereof.

Compounds according to the present invention have a good affinity to theTAARs, especially for TAAR1. Such compounds are useful in the treatmentor prevention of illnesses such as depression, anxiety disorders,bipolar disorder, attention deficit hyperactivity disorder,stress-related disorders, psychotic disorders such as schizophrenia,neurological diseases such as Parkinson's disease, neurodegenerativedisorders such as Alzheimer's disease, epilepsy, migraine, hypertension,substance abuse and metabolic disorders such as eating disorders,diabetes, diabetic complications, obesity, dyslipidemia, disorders ofenergy consumption and assimilation, disorders and malfunction of bodytemperature homeostasis, disorders of sleep and circadian rhythm, andcardiovascular disorders. Preferably, the compounds of the presentinvention are useful in the treatment or prevention of disorders of thecentral nervous system, for example, the treatment or prevention ofdepression, psychosis, Parkinson's disease, anxiety and/or attentiondeficit hyperactivity disorder (ADHD).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound according to formula I,

whereinR is selected from the group consisting of hydrogen, lower alkyl andamino;X is selected from the group consisting of —CH₂—, —CH(lower alkoxy)-,—CH(OH)—, and —NH—;Y is selected from the group consisting of —CH₂, —CH(lower alkyl)-,—CH(lower alkoxy)-, —O—, —S—, —S(O)—, —S(O)₂—, —CH(phenyl)- and —C(loweralkyl)₂-; andAr is selected from the group consisting of phenyl, napthtyl andbenzofuranyl, said phenyl, mapthyl, or benzofuranyl being unsubstitutedor substituted by one or more substituents, each substituent beingindependently selected from the group consisting of lower alkyl, loweralkyl substituted by halogen, halogen, lower alkoxy, lower alkoxysubstituted by halogen, hydroxy, amino, di-alkylamino, morpholinyl,phenyl, benzyl and O-benzyl;with the provisio that, wherein, when X is —NH—, Y is selected from thegroup consisting of —CH₂, —CH(lower alkyl)-, —CH(lower alkoxy)-,—CH(phenyl)- or —C(lower alkyl)₂-; and the further proviso that saidcompound is not

-   5-phenethyl-1H-imidazole,-   5-(2-phenyl-propyl)-1H-imidazole,-   1-(1H-imidazol-4-yl)-2-phenyl-ethanol,-   5-(2,2-diphenyl-ethyl)-1H-imidazole,-   4-(2-m-tolyl-ethyl)-1H-imidazole,-   4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole,-   4-(biphenyl-2-yloxymethyl)-1H-imidazole,-   5-(2-methyl-2-phenyl-propyl)-1H-imidazole,-   4-(2-chloro-phenoxymethyl)-1H-imidazole,-   4-(2-fluoro-phenoxymethyl)-1H-imidazole,-   4-o-tolyloxymethyl-1H-imidazole,-   4-(3-chloro-phenoxymethyl)-1H-imidazole,-   4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or-   5-methyl-4-phenylsulfanylmethyl-1H-imidazole.

The present invention also relates to a pharmaceutically-suitableacid-addition salt of such a compound.

The invention includes all racemic mixtures, all their correspondingenantiomers and/or optical isomers.

In addition, all tautomeric forms of compounds of formula I are alsoencompassed by the present invention.

The present invention is also directed to processes for the preparationof the above compound.

As used herein, the term “halogen” refers to chlorine, iodine, fluorineor bromine.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain hydrocarbon group containing from 1 to 7 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,2-butyl, t-butyl and the like. Preferred lower alkyl groups are groupswith 1 to 4 carbon atoms.

As used herein, the term “lower alkyl substituted by halogen” denotes alower alkyl group as defined above, wherein at least one hydrogen atomis replaced by halogen, for example —CF₃, —CHF₂, —CH₂F, —CH₂CF₃,—CH₂CH₂CF₃, —CH₂CF₂CF₃ and the like.

As used herein, the term “lower alkoxy” denotes a substituent whereinthe alkyl residue is attached to the remainder of the molecule via anoxygen group.

The term “pharmaceutically-suitable acid-addition salt” embraces saltsof a compound of formula I with inorganic and organic acids, such ashydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citricacid, formic acid, fumaric acid, maleic acid, acetic acid, succinicacid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid andthe like, the salt not being toxic and not interfering with the abilityof the compound of formula I to elicit the biological or medicalresponse of a tissue system, animal or human, that is being sought bythe researcher, veterinarian, medical doctor or other clinician.

Preferred compounds of the present invention are those of formula Iwherein X and Y are both —CH₂—. Such compounds include:

-   4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole;-   4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole;-   4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole;-   4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole;-   4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;-   4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole;-   4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole;-   4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole; and    pharmaceutically-suitable acid-addition salts thereof.

Also preferred are compounds of the present invention are those offormula I wherein X is —CH₂— and Y is —CH(lower alkyl), for example thefollowing compounds:

-   4-(2-phenyl-butyl)-1H-imidazole; and    pharmaceutically-suitable acid-addition salts thereof.

Additional preferred are compounds of the present invention are those offormula I wherein X is —CH₂— and Y is —O—, for example the followingcompounds:

-   4-(2,3-dichloro-phenoxymethyl)-1H-imidazole;-   4-(2,3-difluoro-phenoxymethyl)-1H-imidazole;-   4-(3,4-dichloro-phenoxymethyl)-1H-imidazole;-   4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole;-   5-(benzofuran-6-yloxymethyl)-1H-imidazole; and    pharmaceutically-suitable acid-addition salts thereof.

Yet another preferred embodiment of the present invention are compoundsof formula I, wherein X is —CH₂— and Y is —S—, for example the followingcompounds:

-   5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole;-   4-(4-chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole;-   4-(naphthalen-2-ylsulfanylmethyl)-1H-imidazole; and    pharmaceutically-suitable acid-addition salts thereof.

The present compounds of formula I and their pharmaceutically-suitableacid-addition salts can be prepared by various processes, for example,by a process comprising

a) deprotecting a compound of formula

to produce a compound of formula

wherein the definitions are as described above, orb) hydrogenating a compound of formula

to produce a compound of formula

and deprotecting the compound of formula II-1 in a step analogous tostep (a) to produce a compound of formula

wherein Ar is as defined above and R² is hydrogen, lower alkyl or loweralkoxy, orc) alkylating a compound of formula

to produce a compound of formula

and deprotecting the compound of formula II-2 in a step analogous tostep (a) to produce a compound of formula

wherein Ar is as defined above; ord) reacting a compound of formula

and a compound of formula

ArOH  X

to produce a compound of formula

and deprotecting the compound of formula II-3 in a step analogous tostep (a) to produce a compound of formula

wherein the definitions are as described above, ore) reacting a compound of formula

with acetonitrile to produce a compound of formula

and removing the hydroxy group to produce a compound of formula

wherein Ar is as defined above, orreacting a compound of formula

with a compound of formula

to produce a compound of formula

and deprotecting to produce a compound of formula

wherein R is lower alkyl and Ar is as described above, org) reacting a compound of formula

and a compound of formula

ArSH  X′

to produce a compound of formula

and deprotecting the compound of formula II-4 in a step analogous tostep (a) to produce a compound of formula

wherein Ar is as defined above, orh) oxidizing a compound of formula

to produce a compound of formulas

and deprotecting said compound of formula II-5 or formula II-6 in a stepanalogous to step (a) to produce a compound of formulas

respectively, wherein Ar is as defined above; ori) reducing a compound of formula

to produce a compound of formula

and deprotecting the compound of formula II-7 in a step analogous tostep (a) to produce a compound of formula

wherein Ar is as described above and PG is a common N-protecting group.

If desired, the above produced compounds of formula I may be convertedinto pharmaceutically-suitable acid-addition salts.

The following are general schemes which exemplify the use of the aboveprocesses in the production of compounds of formula I. The startingmaterials are either commercially available (e.g., from one or more ofthe following chemical suppliers such as Aldrich, Fluka, Acros,Maybridge, Avocado, TCI, or additional suppliers as indicated indatabases such as Chemical Abstracts [American Chemical Society,Columbus, Ohio] or Available Chemicals Director [Elsevier MDL, SanRamon, California]), are otherwise known in the chemical literature, ormay be prepared in accordance with methods well known in the art.

Procedure A Synthesis of C—C-Linked Compounds

Step A: The Wittig reaction between an aldehyde or a ketone of formulaIII and (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester(IV) can be accomplished by using a base such as NaH, KO-tert-butyl(KOtBu), NaOCH₃, NaOCH₂CH₃, n-butyllithium, LiHMDS, NaHMDS, KHMDS, andLDA in a solvent such as tetrahydrofuran (THF), dioxane, acetonitrile,1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof attemperatures from −78° C.-80° C. for 15 minutes-8 hours and, ifappropriate, optional addition of a crown ether for ylide generation andthen condensing the ylide with the carbonyl compound in the same solventat a temperature between 0 and 80° C. for 1-24 hours. Alternatively, thebase, the carbonyl compound and the optional crown ether can be added tothe reaction mixture at the same time without preformation of the ylideat temperatures from −78° C.-80° C.

Preferred conditions for reactions with aryl ketones are ylide formationat room temperature using KOtBu as the base and THF as the solvent,reacting the phosphonic acid ester for 15 minutes at room temperature,and then condensation with the carbonyl component at 80° C. overnight.Preferred conditions for benzaldehydes are ylide formation in thepresence of the carbonyl compound using KOtBu as the base and THF as thesolvent at 80° C. overnight.

Step B: The reduction of the alkene of formula V can be effected byhydrogenation with hydrogen under normal or elevated pressure or bytransfer hydrogenation using ammonium formiate or cyclohexadiene as ahydrogen source with a catalyst such as PtO₂, Pd—C or Raney nickel insolvents such as methanol (MeOH), ethanol (EtOH), H₂O, dioxane, THF,HOAc, EtOAc, CH₂Cl₂, CHCl₃, DMF or mixtures thereof. Alternatively, thereduction of the alkene can be effected by Mg in MeOH or by LiAlH₄ inTHF or diethylether.

The preferred procedure for trisubstituted alkenes is hydrogenation atnormal pressure in MeOH/CH₂Cl₂ using 10% Pd/C as catalyst. The preferredprocedure for disubstituted alkenes is hydrogenation at normal pressurein MeOH/CHCl₃/AcOH using 10% Pd/C as catalyst. Both conditions may leadto partial loss of the trityl protecting group. In this case the mixtureof protected and unprotected products is subjected directly toconditions C.

Step C: The cleavage of the trityl group can be effected with a mineralacid such as HCl, H₂SO₄ or H₃PO₄ or a organic acid such as CF₃COOH,CHCl₂COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH₂Cl₂,CHCl₃, THF, MeOH, EtOH or H₂O at 0 to 60° C.

Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.

Procedure B Synthesis of C—C-Linked Compounds with Alkoxy Substituent inα Position to Imidazoles

Step A: The formylation of2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethyl-amide(VII) can be effected by deprotonation with a strong base such asn-butyllithium, s-butyllithium or t-butyllithium and optionally anadditive such as tetramethylethylene diamine or pentamethyl diethylenetriamine in a solvent such as THF or diethylether at −78° C.-−40° C.,followed by quenching the anion with a formylating electrophile such asDMF at −78° to room temperature for 1-24 hours.

Preferred conditions are deprotonation with n-butyllithium at −78° C.for 10 minutes, then reaction with DMF at −78° C. for 2 hours.

Step B: The Grignard reaction of the protected formyl imidazole (VII)with an aryl magnesium chloride or bromide (VIII) can be effected byadding a solution of the Grignard reagent (commercially available orprepared form a benzyl chloride or bromide and Mg by standard methods)in a solvent such as diethylether, THF or benzene to a solution of thealdehyde in one of the previously mentioned solvents at −20° C. to roomtemperature and letting the two components react at room temperature toreflux temperature for 1-24 hours.

Preferred conditions involve addition of the Grignard reagent indiethylether to a solution of aldehyde in THF at room temperature andreaction at room temperature overnight.

Step C: The alkylation of the alcohol of formula IX can be accomplishedby deprotonation of the hydroxy group with a base such as NaH, KH,n-butyllithium, KOtBu, KOH or aqueous NaOH and KOH in the presence of aphase transfer catalyst (tetraalkylammonium salts) in a suitable solventsuch as THF, DMF, DMSO, toluene or 1,2-dimethoxyethane at −78° C. toroom temperature for 30 minutes-2 hours and subsequent addition of analkyl halide.

Preferred conditions are deprotonation with NaH in THF at roomtemperature for 1 hour and alkylation with an alkyl iodide at roomtemperature overnight.

Step D: The simultaneous cleavage of both protecting groups (II-2) canbe achieved in the presence of a mineral acid such as HCl, HBr or H₂SO₄in a solvent such as EtOH, MeOH, H₂O or THF at room temperature refluxtemperature for 1-24 hours.

Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.

Procedure C Synthesis of C—O-Linked Compounds

Step A: The alkylation of a substituted phenol with4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using abase such as K₂CO₃, Cs₂CO₃, Na₂CO₃, NaHCO₃, aqueous NaOH, KOH, LiOH,NaH, NaOCH₃, NaOCH₂CH₃ or triethylamine in a solvent such as acetone,DMF, DMSO, acetonitrile, toluene, EtOH, and MeOH and optionally ifappropriate a phase transfer catalyst such as tetrabutylammonium bromideor an additive such as a crown ether, tetrabutylammonium iodide orpotassium iodide at room temperature 120° C. for 1-24 hours.

Preferred conditions are K₂CO₃ in DMF at 80° C. for 5 hours.

Step B: The cleavage of the trityl group can be effected with a mineralacid such as HCl, H₂SO₄ or H₃PO₄ or a organic acid such as CF₃COOH,CHCl₂COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH₂Cl₂,CHCl₃, THF, MeOH, EtOH or H₂O at 0 to 60° C. Preferred conditions are 2NHCl in EtOH at reflux for 1-3 hours.

Procedure D Synthesis of C—C-linked 2-methyl-4-imidazoles

An appropriate olefin such as aryl-1-butene (XII) can be reacted atlower temperature with a nitrile such as acetonitrile and nitrosoniumfluoroborate to form an imidazole-N-oxide according to Scheinbaum et al.(Tetrahedron Lett. 1971, p. 2205). To form the imidazole derivative 1-4the hydroxyfunction can be removed by various reducing agents such asRed-Al, Titanium(III)-salts, Lithiumaluminiumhydride or others asdescribed by Lipshutz et al. in Tetrahedron Lett. 25, 1984, p. 1319.

Procedure E Synthesis of C—C-linked 2-amino-4-imidazoles

An alpha-bromoketone of formula XIII is reacted with an protectedguanidine such as acetylguanidine (XIV) in a solvent such asdimethylformamide followed by deprotection of the amino group to form2-aminoimidazole 1-5. This deprotection can be achieved for instance byacid or base catalysed hydrolysis. In the case where the protectinggroup is an acetyl group, deprotection is preferably achieved bytreatment with hydrochloric acid in a polar solvent such as water,alkohols or mixtures of water and alkohols.

Procedure F Synthesis of C—S-Linked Compounds

Step A: The alkylation of a substituted phenol (X) with4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using abase such as K₂CO₃, Cs₂CO₃, Na₂CO₃, NaHCO₃, aqueous NaOH, KOH, LiOH,NaH, NaOCH₃, NaOCH₂CH₃ or triethylamine in a solvent such as acetone,DMF, DMSO, acetonitrile, toluene, EtOH or MeOH and optionally ifappropriate a phase transfer catalyst such as tetrabutylammonium bromideor an additive such as a crown ether, tetrabutylammonium iodide orpotassium iodide at room temperature to 120° C. for 1-24 hours.

Preferred conditions are K₂CO₃ in DMF at 80° C. for 5 hrs.

Step B: The cleavage of the trityl group can be effected with a mineralacid such as HCl, H₂SO₄ or H₃PO₄ or a organic acid such as CF₃COOH,CHCl₂COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH₂Cl₂,CHCl₃, THF, MeOH, EtOH or H₂O at 0 to 60° C.

Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs.

Step C: The oxidation of the thioether (II-4) to the correspondingsulfoxide (II-5) can be accomplished by oxidants such as mCPBA,isopropyl 2-iodoxybenzoate, oxone or natriumperiodate in a solvent suchas CH₂Cl₂, dichloroethane, toluene, acetonitrile, MeOH at temperaturesfrom 0° C. to reflux.

Preferred conditions are 1 equivalent of mCPBA in CH₂Cl₂ at 0° C. toroom temperature for 1-5 hours.

Step D: The oxidation of the thioether (II-4) to the correspondingsulfoxide (II-6) can be accomplished by oxidants such as mCPBA, H₂O₂,oxone or sodium wolframate in a solvent such as CH₂Cl₂, dichloroethane,toluene, acetonitrile, THF, acetone, or MeOH at temperatures from 0° C.to reflux.

Preferred conditions are 2 equivalent of mCPBA in CH₂Cl₂ at 0° C. toroom temperature for 1 to 5 hrs.

Procedure E Synthesis of C—N-Linked Compounds

Step A: The coupling of a substituted arylcarboxylic acid (XVI) with asuitably protected 4-amino-imidazole compound (XVII) to afford an amidecompound (IXX) can be accomplished using a coupling agent such as2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) or 2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU) oro-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluroniumhexafluorophosphate (HATU) and a base such as triethylamine orethyldiisopropylamine in a solvent such as THF, DMF, or dichloromethane.Suitable nitrogen protecting groups include tert-butoxycarbamate (BOC),trityl, dimethylaminosulfonyl and trimethylsilyl-ethyl (SEM). Preferredconditions are TBTU and ethyldiisopropylamine in DMF at 40° C. for 16hrs, and a preferred protecting group is trityl.

Step B: The coupling of a substituted arylcarboxylic acid chloride(XVIII) with a suitably protected 4-amino-imidazole compound (XVII) toafford an amide compound (IXX) can be accomplished using a base such aspyridine, triethylamine or ethyldiisopropylamine in a solvent such asTHF, DMF or dichloromethane and optionally using a catalyst such asN,N-dimethylformamide or 4-N,N-dimethylaminopyridine (DMAP)

Preferred conditions are triethylamine in dichloromethane at roomtemperature for 1 hour, and a preferred protecting group is trityl.

Step C: The reduction of an amide (IXX) to an amine (II-7) can beaccomplished using a metal hydride reducing agent such as lithiumaluminium hydride or a borane reagent such as borane-tetrahydrofurancomplex in a solvent such as dioxane, ether or tetrahydrofuran atelevated temperature.

Preferred conditions are lithium aluminium hydride in tetrahydrofuran atreflux temperature for 16 hours.

Step D: The deprotection conditions depend on the nature of theprotecting group employed and many methods are well known in the art.

In the case of the trityl protecting group, preferred deprotectionconditions are 4 M aqueous hydrochloric acid in dioxane at roomtemperature for 1-2 hours.

Isolation and Purification of the Compounds

Isolation and purification of the compounds and intermediates describedherein can be effected, if desired, by any suitable separation orpurification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography,thick-layer chromatography, preparative low or high-pressure liquidchromatography or a combination of these procedures. Specificillustrations of suitable separation and isolation procedures can be hadby reference to the preparations and examples herein below. However,other equivalent separation or isolation procedures could, of course,also be used. Racemic mixtures of chiral compounds of formula I can beseparated using chiral HPLC.

Salts of Compounds of Formula I

The compounds of formula I are basic and may be converted to acorresponding acid-addition salt. The conversion is accomplished bytreatment with at least a stoichiometric amount of an appropriate acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid,malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid andthe like. Typically, the free base is dissolved in an inert organicsolvent such as diethyl ether, ethyl acetate, chloroform, ethanol ormethanol and the like, and the acid added in a similar solvent. Thetemperature is maintained between 0° C. and 50° C. The resulting saltprecipitates spontaneously or may be brought out of solution with a lesspolar solvent.

The acid-addition salts of the basic compounds of formula I may beconverted to the corresponding free bases by treatment with at least astoichiometric equivalent of a suitable base such as sodium or potassiumhydroxide, potassium carbonate, sodium bicarbonate, ammonia, and thelike.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically-suitableacid-addition salt thereof, and a therapeutically-inert carrier.Processes for the production of such a composition are also aspects ofthe present invention. Such a process comprises bringing one or morecompounds of formula I and/or a pharmaceutically-suitable salt(s)thereof and, if desired, one or more other therapeutically-valuablesubstances into a galenical administration form together with one ormore therapeutically-inert carriers.

The term “therapeutically-inert carrier” means that the carrier is nottoxic and does not interfere with the ability of the active compound(s)to elicit the biological or medical response of a tissue system, animalor human that is being sought by the researcher, veterinarian, medicaldoctor or other clinician. The therapeutically-inert carrier for use inthe composition of the present invention may be inorganic or organic.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatine capsules. Suitablecarriers for soft gelatine capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatine capsules. Suitable carriers forthe production of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical composition can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. The composition can also contain stillother therapeutically valuable substances.

The pharmaceutical composition of the present invention can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, and parenterally, e.g. in the form ofinjection solutions.

The present invention relates also to a method for treating orpreventing a disease or disorder in a patient comprising administering atherapeutically-effective amount of a compound of the present inventionto a patient. A “therapeutically-effective amount” is the amount of thesubject compound that will elicit the biological or medical response ofa tissue system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. The above method mayinvolve the administration of a composition which comprises atherapeutically-effective amount of the compound such as the compositiondescribed above.

The therapeutically-effective amount can vary within wide limits andwill, of course, have to be adjusted to the individual requirements ineach particular case. In the case of oral administration the dosage foradults can vary from about 0.01 mg to about 1000 mg per day of acompound of general formula I or of the corresponding amount of apharmaceutically-suitable salt thereof. The daily dosage may beadministered as single dose or in divided doses and, in addition, theupper limit can also be exceeded when this is found to be indicated.

EXAMPLES

The following examples illustrate the invention but are not intended tolimit its scope.

Example 1 4-(2-Phenyl-butyl)-1H-imidazole a)4-(2-Phenyl-but-1-enyl)-1-trityl-1H-imidazole

To a stirred solution of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (1.24 g; CAS 473659-21-1) at room temperature (r.t.)in THF (20 ml) under an argon atmosphere was added potassiumtert-butylate (301 mg). After 15 minutes stirring at room temperature,propiophenone (0.3 ml) was added in one portion. The mixture was heatedto 80° C. and stirring at that temperature was continued for 2 days. Thecompact suspension was cooled to r.t. and the solid was filtered off andwashed with THF. The filtrate was concentrated to leave a dark violetviscous oil. This was taken up in ethyl acetate (EtOAc) and washed withbrine. The aqueous phase was back extracted with EtOAc. The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was purified by column chromatography(silica gel; gradient cyclohexane->cyclohexane/EtOAc 3:2) to give4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (269 mg; not completelypure) as an off-white solid. MS (ISP): 243.2 ([Trt]⁺)

b) 4-(2-Phenyl-butyl)-1H-imidazole

To a stirred solution of 4-(2-phenyl-but-1-enyl)-1-trityl-1H-imidazole(260 mg) at r.t. in methanol (5 ml) and dichloromethane (2 ml) under anargon atmosphere was added 10% Pd/C (26 mg). The mixture was thenstirred at r.t. under a hydrogen atmosphere for 17 hours. The catalystwas filtered off and washed with methanol. The filtrate wasconcentrated. The crude product was purified by column chromatography(silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH 9:1 to give4-(2-phenyl-butyl)-1H-imidazole (18 mg) as colorless gum. MS (ISP):201.3 ([M+H]⁺)

Example 2 4-(3-Methyl-2-phenyl-butyl)-1H-imidazole a)4-(3-Methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole

To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (921 mg; CAS 473659-21-1) at r.t. in THF (20 ml)under an argon atmosphere was added potassium tert-butylate (241 mg).The mixture was then stirred at r.t. for 15 minutes, andisobutyrophenone (0.25 ml) was added in one portion. The mixture (clearbrown orange solution) was heated to 80° C. for 21 hours. The reactionmixture was filtered and the cake was washed with EtOAc. The filtratewas concentrated. The crude product was purified by columnchromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc1:1) to give 4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (91mg; not completely pure) as orange sticky solid. MS (ISP): 243.2([Trt]⁺)

b) 4-(3-Methyl-2-phenyl-butyl)-1-trityl-1H-imidazole

To a stirred solution of4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (87 mg) at r.t.in methanol (4 ml) and CH₂Cl₂ (1 ml) under an argon atmosphere was addedthe 10% Pd/C (10 mg). The mixture was then stirred at r.t. under ahydrogen atmosphere for 38 hours. The catalyst was filtered off andwashed with MeOH. The filtrate was concentrated to leave4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (82 mg) of anoff-white sticky solid which was used in the next step without furtherpurification. MS (ISP): 243.2 ([Trt]⁺)

c) 4-(3-Methyl-2-phenyl-butyl)-1H-imidazole

To a stirred suspension of4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (80 mg) at r.t. inethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). Themixture (suspension) was heated to reflux (turning to a clear lightyellow solution when reaching 90° C.) and stirred for 2 hours and 30minutes, then cooled to r.t. and concentrated to leave a light brownsticky solid. This was taken up in H₂O and basified to pH>12 by theaddition of 4 N NaOH. The product was extracted with CH₂Cl₂/MeOH 9:1.The combined organics were dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography (silica gel;gradient: CH₂Cl₂->CH₂Cl₂/MeOH 85:15) to give4-(3-methyl-2-phenyl-butyl)-1H-imidazole (8 mg) as colorless gum. MS(ISP): 215.4 ([M+H]⁺)

Example 3 4-(3,3-Dimethyl-2-phenyl-butyl)-1H-imidazole a)4-(3,3-Dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole

To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (341 mg; CAS 473659-21-1) at r.t. in THF (7.5 ml)under an argon atmosphere was added potassium tert-butylate (83 mg). Themixture was then stirred at r.t. for 15 minutes, and2,2-dimethylpropiophenone (0.1 ml) was added in one portion. The mixture(clear brown orange solution) was heated to 80° C. and stirring at thattemperature was continued for 24 hours. The reaction mixture wasdirectly adsorbed on silica gel. The product was isolated bychromatography (gradient: cyclohexane->cyclohexane/EtOAc 65:35) to give4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (135 mg; notcompletely pure) as light yellow solid. MS (ISP): 243.2 ([Trt]⁺)

b) 4-(3,3-Dimethyl-2-phenyl-butyl)-1H-imidazole

To a stirred solution of4-(3,3-dimethyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (121 mg) atr.t. in methanol (5 ml) and dichloromethane (1 ml) under an argonatmosphere was added 10% Pd/C (12 mg). The mixture was stirred under ahydrogen atmosphere (balloon) for 17 hours. The catalyst was filteredoff and washed with methanol. The filtrate was concentrated. The crudeproduct was purified by column chromatography (silica gel; gradient:CH₂Cl₂->CH₂Cl₂/MeOH 9:1) to give4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole (25 mg) as colorless gum.MS (ISP): 229.4 ([M+H]⁺)

Example 4 4-(1-Methoxy-2-phenyl-ethyl)-1H-imidazole a)2-(tert-Butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic aciddimethylamide

To a stirred, cooled (−78° C.) solution of2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide(1.02 g; CAS 129378-52-5) in THF (20 ml) under an argon atmosphere wasadded dropwise butyl lithium (3.3 ml; 1.6 M solution in hexanes) over aperiod of 10 minutes. After 30 minutes of stirring, DMF (1.3 ml) wasadded over a period of 5 minutes and the mixture (clear light yellowsolution) was stirred at −78° C. for another 2 hours. The mixture wasquenched with saturated aqueous NH₄Cl and diluted with EtOAc. Theaqueous phase was back extracted with EtOAc. The combined organics werewashed with H₂O and brine, dried over MgSO₄, filtered and concentratedto give 2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonicacid dimethylamide (1.22 g) as viscous orange oil which was used in thenext reaction step without further purification. MS (ISP): 318.3([M+H]⁺)

b)2-(tert-Butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide

Benzyl bromide (4.1 ml) was added dropwise to a stirred suspension ofmagnesium (1.01 g) in diethyl ether (10 ml). When the vigorouslyexothermic reaction was complete, the supernatant solution was decantedfrom the solid and kept in the fridge, ready for use. An aliquot of thissolution (1 ml) was added dropwise (exothermic!) to a cooled (0° C., icebath) stirred solution of2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic aciddimethylamide (725 mg) at r.t. in THF (5 ml) under an argon atmosphere.When addition was complete, stirring at r.t. was continued overnight.The mixture was quenched by the addition of saturated aqueous NH₄Cl andextracted with EtOAc. The aqueous phase was back extracted with EtOAc.The combined organics were washed with H₂O and brine, dried over MgSO₄,filtered and concentrated. The crude product was purified by columnchromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc25:75) to give2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide (168 mg) as light yellow solid. MS (ISP): 410.1([M+H]⁺)

c)2-(tert-Butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide

To a stirred solution of2-(tert-butyl-dimethyl-silanyl)-4-(1-hydroxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide (160 mg) at r.t. in THF (5 ml) under an argonatmosphere was added NaH (18 mg; 55% dispersion in mineral oil) in oneportion. After 1 hour stirring at r.t., MeI (0.04 ml) was added andstirring at r.t. was continued overnight. The mixture was diluted withEtOAc and washed with H₂O. The aqueous phase was back extracted withEtOAc. The combined organics were washed with H₂O and brine, dried overMgSO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel; gradient:cyclohexane->cyclohexane/EtOAc 65:35) to give2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide (111 mg) as light yellow viscous oil. MS (ISP): 424.3([M+H]⁺)

d) 4-(1-Methoxy-2-phenyl-ethyl)-1H-imidazole

To a stirred suspension of2-(tert-butyl-dimethyl-silanyl)-4-(1-methoxy-2-phenyl-ethyl)-imidazole-1-sulfonicacid dimethylamide (105 mg) at r.t. in ethanol (3 ml) under an argonatmosphere was added 2 N HCl (3 ml). The mixture was heated to refluxfor 3 hours. The mixture was cooled to r.t. and concentrated to leave alight yellow solid which was taken up in H2O and brought to pH 12 by theaddition of 4 N NaOH. The product was extracted with CH₂Cl₂/MeOH 4:1.The combined organics were dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography (silica gel;gradient: CH₂Cl₂->CH₂Cl₂/MeOH 9:1) to give4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole (38 mg) as white solid. MS(ISP): 203.4 ([M+H]⁺)

Example 5 4-[2-(2-Chloro-phenyl)-ethyl]-1H-imidazole a)4-[2-(2-Chloro-phenyl)-vinyl]-1-trityl-1H-imidazole

To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (448 mg; CAS 473659-21-1) at r.t. in THF (7 ml) underan argon atmosphere were added potassium tert-butylate (109 mg) and2-chlorobenzaldehyde (114 mg). The mixture (clear brown orange solution)was heated to 80° C. over night. The reaction mixture was cooled to r.tand concentrated. The crude product was purified by columnchromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc3:2) to give 4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329mg) as off-white solid. MS (ISP): 243.3 ([Trt]⁺)

b) 4-[2-(2-Chloro-phenyl)-ethyl]-1H-imidazole

To a stirred mixture of4-[2-(2-chloro-phenyl)-vinyl]-1-trityl-1H-imidazole (329 mg) at r.t. inethanol (7 ml) and chloroform (3 ml) under an argon atmosphere wereadded acetic acid (0.2 ml) and 10% Pd/C (30 mg). The mixture washydrogenated (ambient pressure) over night. The catalyst was filteredoff and washed with ethanol. The mixture was concentrated to leave alight brown gum. This material was taken up in ethanol (3 ml) and 2 NHCl (3 ml) and heated to reflux for 3 h. Then, the mixture was cooled tor.t., concentrated. The residual solid was taken up in 1 N NaOH (10 ml)and extracted with CH₂Cl₂/MeOH 4:1. The combined organics were driedover MgSO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH 9:1) togive 4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole (44 mg) as light browngum. MS (ISP): 207.1 ([M+H]⁺)

Example 6 4-[2-(2-Ethyl-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with2-ethylbenzaldehyde and then converted to4-[2-(2-ethyl-phenyl)-ethyl]-1H-imidazole, as a colorless viscous oil.MS (ISP): 201.3 ([M+H]⁺)

Example 7 4-[2-(2-Trifluoromethyl-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with2-(trifluormethyl)benzaldehyde and then converted to4-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-imidazole, as a colorlessviscous oil. MS (ISP): 241.3 ([M+H]⁺)

Example 8 4-[2-(2-Methoxy-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with2-methoxybenzaldehyde and then converted to4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole, as a colorless viscous oil.MS (ISP): 203.1 ([M+H]⁺)

Example 9 {2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with2-(N,N-dimethylamino)benzaldehyde and then converted to{2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine, as a lightyellow viscous oil. MS (ISP): 216.3 ([M+H]⁺)

Example 10 4-{2-[2-(1H-Imidazol-4-yl)-ethyl]-phenyl}-morpholine

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with2-morpholinobenzaldehyde and then converted to4-{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-morpholine, as a light yellowviscous oil. MS (ISP): 258.3 ([M+H]⁺)

Example 11 4-[2-(3-Chloro-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3-chlorobenzaldehyde and then converted to4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole, as an off-white solid. MS(ISP): 207.1 ([M+H]⁺)

Example 12 4-[2-(3-Fluoro-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3-fluorobenzaldehyde and then converted to4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole, as an off-white solid. MS(ISP): 191.1 ([M+H]⁺)

Example 13 4-[2-(3-Trifluoromethyl-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3-(trifluoromethyl)benzaldehyde and then converted to4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole, as an off-whiteviscous oil. MS (ISP): 241.1 ([M+H]⁺)

Example 14 4-[2-(3-Methoxy-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3-methoxybenzaldehyde and then converted to4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole, as an off-white solid. MS(ISP): 203.3 ([M+H]⁺)

Example 15 4-[2-(3-Trifluoromethoxy-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3-(trifluoromethoxy)benzaldehyde and then converted to4-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-imidazole, as a light yellowviscous oil. MS (ISP): 257.3 ([M+H]⁺)

Example 16 4-[2-(4-Chloro-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with4-chlorobenzaldehyde and then converted to4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole, as an off-white solid. MS(ISP): 207.1 ([M+H]⁺)

Example 17 4-[2-(3,5-Dichloro-phenyl)-ethyl]-1H-imidazole

In analogy to example 5, (1-trityl-1H-imidazol-4-ylmethyl)-phosphonicacid diethyl ester (CAS 473659-21-1) was reacted with3,5-dichlorobenzaldehyde and then converted to4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole, as an off-white solid.MS (ISP): 241.1 ([M+H]⁺)

Example 18 2-Methyl-5-phenethyl-1H-imidazole a)2-Methyl-5-phenethyl-imidazol-1-ol

To a solution of nitrosonium tetrafluoroborate (0.564 g, 4.83 mmol) inacetonitrile (8 ml) 4-phenyl-1-butene was added at −30° C. The mixturewas stirred for 1 hour at this temperature, then 0.5 ml of water wasadded carefully. At room temperature saturated ammonium chloridesolution was added and the acetonitrile was evaporated in vacuo. The pHof the remaining aqueous solution was adjusted to neutral with a smallamount of sodium hydroxide and extracted with dichloromethane. Theorganic layer was separated, dried over magnesium sulfate andevaporated. The residue was purified using flash chromatography (SiO₂,dichloromethane/methanol=9:1) to yield an off-white solid (0.245 g,17%); MS (ISP): 202.9 ([M+H]⁺)

b) 2-Methyl-5-phenethyl-1H-imidazole

To a solution of 2-methyl-5-phenethyl-imidazol-1-ol (0.20 g, 1.0 mmol)in methanol (3.5 ml) titanium(III)-chloride solution (2.5 ml, 15%) wasadded and the mixture was stirred overnight at room temperature. Firstsaturated sodium bicarbonate solution then diluted sodium hydroxidesolution was added to achieve a basic pH. The mixture was extractedtwice with dichloromethane, the combined organic layers were dried overmagnesium sulfate and evaporated. The residue was purified by columnchromatography (dichloromethane/methanol=9:1) to yield a white solid(0.14 mg, 75%); MS (EI): 186.1 (M^(+.)).

Example 19 5-Phenethyl-1H-imidazol-2-ylamine

To a solution of 1-acetylguanidine (1.34 g, 13.2 mmol) indimethylformamide (7 ml) a solution of 1-bromo-4-phenyl-butan-2-one (1.5g, 6.6 mmol) in dimethylformamide (7 ml) was added at 0° C. The mixturewas stirred overnight at room temperature and then the solvent wasevaporated. Upon addition of ethyl acetate/heptane (1:1) a white solidwas formed that was filtered off and washed with ethyl acetate/heptane(1:1). After drying in vacuo the solid was dissolved in a mixture ofconcentrated hydrochloric acid (2 ml) and methanol (4 ml) and stirredfor 2.5 hours at 85° C. The solvent was evaporated and the residue waspurified by chromatography (column: Isolute® Flash-NH₂ from Separtis;eluent: ethyl acetate/methanol=1:1) to yield a light yellow solid (0.063mg, 5%); MS (EI): 187.2 (M^(+.)).

Example 20 4-(2,3-Dichloro-phenoxymethyl)-1H-imidazole a)4-(2,3-Dichloro-phenoxymethyl)-1-trityl-1H-imidazole

To a stirred solution of 4-chloromethyl-1-trityl-1H-imidazole (400 mg;CAS 103057-10-9) at r.t. in DMF (5 ml) under an argon atmosphere wereadded 2,3-dichlorophenol (273 mg) and K₂CO₃ (385 mg). The reactionmixture was heated to 80° C. for 5 hours, then cooled to r.t., dilutedwith EtOAc and washed with 1 N NaOH. The aqueous phase was backextracted with EtOAc. The combined organics were washed with H₂O andbrine, dried over MgSO₄, filtered and concentrated. The crude productwas purified by column chromatography (silica gel; gradient:cyclohexane->cyclohexane/EtOAc 1:1) to give4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (360 mg) as whitesolid. MS (ISP): 243.3 ([Trt]⁺)

b) 4-(2,3-Dichloro-phenoxymethyl)-1H-imidazole

To a stirred suspension of4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (150 mg) at r.t. inethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). Themixture was heated to reflux for 6 hours, then concentrated to leave anoff-white solid. This was taken up in saturated aqueous Na₂CO₃ andextracted with CH₂Cl₂/MeOH 4:1. The combined organics were dried overMgSO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH 4:1) togive 4-(2,3-dichloro-phenoxymethyl)-1H-imidazole (65 mg) as white solid.MS (ISP): 243.4 ([M+H]⁺)

Example 21 4-(2-Ethyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-ethylphenol and then converted to4-(2-ethyl-phenoxymethyl)-1H-imidazole, as awaxy off-white solid. MS(ISP): 203.1 ([M+H]⁺)

Example 22 4-(2-Isopropyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-isopropylphenol and then converted to4-(2-isopropyl-phenoxymethyl)-1H-imidazole, as a waxy off-white solid.MS (ISP): 217.4 ([M+H]⁺)

Example 23 4-(2-Trifluoromethyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-trifluoromethylphenol and then convertedto 4-(2-trifluoromethyl-phenoxymethyl)-1H-imidazole, as a white solid.MS (ISP): 243.4 ([M+H]⁺)

Example 24 4-(2-Benzyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-benzylphenol and then converted to4-(2-benzyl-phenoxymethyl)-1H-imidazole, as a waxy white solid. MS(ISP): 265.1 ([M+H]⁺)

Example 25 4-(2-Methoxy-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-methoxyphenol and then converted to4-(2-methoxy-phenoxymethyl)-1H-imidazole as an off-white amorphoussolid. MS (ISP): 205.1 ([M+H]⁺)

Example 26 4-(2-Isopropoxy-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-isopropoxyphenol and then converted to4-(2-isopropoxy-phenoxymethyl)-1H-imidazole as an off-white solid. MS(ISP): 233.3 ([M+H]⁺)

Example 27 4-(2-Trifluoromethoxy-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-trifluoromethoxyphenol and thenconverted to 4-(2-trifluoromethoxy-phenoxymethyl)-1H-imidazole as anoff-white solid. MS (ISP): 259.1 ([M+H]⁺)

Example 28 4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole a)4-(2-Benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole

In analogy to example 20.a., 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2-benzyloxyphenol to give4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole as a yellow viscousoil. MS (ISP): 523.5 ([M+H]⁺)

b) 4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole

A solution of 4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (34mg) in MeOH (2 ml) was treated with AcOH (0.1 ml) and was heated to 70°C. for 5 hours. The mixture was concentrated. The crude product waspurified by column chromatography to give4-(2-benzyloxy-phenoxymethyl)-1H-imidazole (11 mg) as a colorlessamorphous solid. MS (ISP): 281.4 ([M+H]⁺)

Example 29 2-(1H-Imidazol-4-ylmethoxy)-phenol

Under conditions as described in example 20.b,4-(2-benzyloxy-phenoxymethyl)-1-trityl-1H-imidazole (example 28.a) wasconverted to 2-(1H-Imidazol-4-ylmethoxy)-phenol as an off-white solid.MS (ISP): 191.4 ([M+H]⁺)

Example 30 4-(3-Trifluoromethyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-trifluoromethylphenol and then convertedto 4-(3-trifluoromethyl-phenoxymethyl)-1H-imidazole as a white solid. MS(ISP): 243.3 ([M+H]⁺)

Example 31 4-(3-Trifluoromethoxy-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-trifluoromethoxyphenol and thenconverted to 4-(3-trifluoromethoxy-phenoxymethyl)-1H-imidazole as acolorless oil. MS (ISP): 259.0 ([M+H]⁺)

Example 32 [3-(1H-Imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-dimethylaminophenol and then convertedto [3-(1H-imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine as an off-whitesolid. MS (ISP): 218.4 ([M+H]⁺)

Example 33 4-[-(1H-Imidazol-4-ylmethoxy)-phenyl]-morpholine

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-morpholinophenol and converted to4-[3-(1H-imdazol-4-ylmethoxy)-phenyl]-morpholine as a white solid. MS(ISP): 260.3 ([M+H]⁺)

Example 34 4-(2,6-Diethyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2,6-diethylphenol and converted to4-(2,6-diethyl-phenoxymethyl)-1H-imidazole as a colorless oil. MS (ISP):231.4 ([M+H]⁺)

Example 35 4-(2,3-Difluoro-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 2,3-difluorophenol and converted to4-(2,3-difluoro-phenoxymethyl)-1H-imidazole as a white solid. MS (ISP):211.1 ([M+H]⁺)

Example 36 4-(3,4-Dichloro-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3,4-dichlorophenol and converted to4-(3,4-dichloro-phenoxymethyl)-1H-imidazole as a white solid. MS (ISP):243.1 ([M+H]⁺)

Example 37 4-(4-Chloro-3-fluoro-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 4-chloro-3-fluorophenol and converted to4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole as a white solid. MS(ISP): 227.1 ([M+H]⁺)

Example 38 4-(3,4-Difluoro-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3,4-difluorophenol and converted to4-(3,4-difluoro-phenoxymethyl)-1H-imidazole as a white solid. MS (ISP):211.1 ([M+H]⁺)

Example 39 5-(Benzofuran-6-yloxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 6-hydroxybenzofurane and converted to5-(benzofuran-6-yloxymethyl)-1H-imidazole.

Example 40 4-(3-Chloro-5-fluoro-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 3-chloro-5-fluorophenol and converted to4-(3-chloro-5-fluoro-phenoxymethyl)-1H-imidazole as an off-whiteamorphous solid. MS (ISP): 227.1 ([M+H]⁺)

Example 41 5-(4-Bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole

In analogy to example 20, 4-chloromethyl-1-trityl-1H-imidazole (CAS103057-10-9) was reacted with 4-bromo-2,6-dimethylphenol and convertedto 5-(4-bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole.

Example 42 5-(2,3-Dichloro-phenylsulfanylmethyl)-1-imidazole a)5-(2,3-Dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole

A solution of 4-chloromethyl-1-trityl-1H-imidazole (600 mgl; CAS103057-10-9) in DMF (12 ml) was treated under an Argon atmosphere withpotassium carbonate (578 mg) and 2,3-dichlorobenzenethiol (449 mg). Thereaction mixture was heated to 80° C. for 5 hours, then cooled to r.t.,taken up in water and extracted with EtOAc. The organic layer was washedwith water, dried over MgSO4 and concentrated. The crude product waspurified by column chromatography (silica gel; gradient:cyclohexane->cyclohexane/EtOAc 1:1) to give5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole (564 mg) asan off-white solid. MS (ISP): 243.3 ([Trt]⁺)

b) 5-(2,3-Dichloro-phenylsulfanylmethyl)-1-imidazole

In analogy to example 20.b,5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole was convertedto 5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole as an off-whitesolid. MS (ISP): 259.0 ([M+H]⁺)

Example 43 5-(2,3-Dichloro-benzenesulfinylmethyl)-1-imidazole a)5-(2,3-Dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole

A solution of 5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole(250 mg; example 42.a) in CH₂Cl₂ (20 ml) was cooled under an Argonatmosphere to 0° and treated with meta-chloroperbenzoic acid (86 mg).The reaction mixture was stirred for 3 hours at 0° C., thenconcentrated. The crude product was purified by column chromatography(silica gel; gradient: CH₂Cl₂->CH₂Cl₂/MeOH 98:2) to give5-(2,3-dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole (121 mg) asa white solid. MS (ISP): 517.3 ([M+H]⁺)

b) 5-(2,3-Dichloro-benzenesulfinylmethyl)-1-imidazole

In analogy to example 20.b,5-(2,3-dichloro-benzenesulfinylmethyl)-1-trityl-1-imidazole wasconverted to 5-(2,3-dichloro-benzenesulfinylmethyl)-1-imidazole as awhite solid. MS (ISP): 275.1 ([M+H]⁺)

Example 44 5-(2,3-Dichloro-benzenesulfonylmethyl)-1H-imidazole

In analogy to example 43, but using 2 equivalents ofmeta-chloroperbenzoic acid in the first reaction step,5-(2,3-dichloro-phenylsulfanylmethyl)-1-trityl-1-imidazole (250 mg;example 42.a) was converted to5-(2,3-dichloro-benzenesulfonylmethyl)-1H-imidazole as a white solid. MS(ISP): 291.0 ([M+H]⁺)

Example 45 4-Benzene sulfinylmethyl-5-methyl-1H-imidazole

The title compound was prepared in analogy to example 43 using4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS 106147-85-7) for thealkylation of benzenethiol.

Example 46 4-(4-Chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole

The title compound was prepared in analogy to example 42 using4-chloromethyl-5-methyl-1-trityl-1H-imidazole (CAS 106147-85-7) for thealkylation of 4-chlorobenzenethiol.

Example 47 4-(Naphthalen-2-ylsulfanylmethyl)-1H-imidazole

The title compound was prepared in analogy to example 42 starting fromnaphthalene-2-thiol.

Example 48 Benzyl-(1H-imidazol-4-yl)-amine hydrochloride a)N-(1-Trityl-1H-imidazol-4-yl)-benzamide

To a solution of 4-amino-1-tritylimidazole (0.30 g, 0.92 mmol) indichloromethane (4 ml) were added sequentially triethylamine (0.19 ml,1.37 mmol) and benzoyl chloride (0.13 ml, 1.12 mmol). The reactionmixture was stirred at room temperature for 30 minutes, then dilutedwith dichloromethane and washed sequentially with water, saturated aq.NaHCO₃ solution, water and saturated brine. The organic layer wasseparated, dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (eluant:methanol/dichloromethane 0:100 to 10:90) to yield the title compound asan orange solid (0.36 g, 92%); MS (ISP): 430.3 ([M+H]⁺).

b) Benzyl-(1-trityl-1H-imidazol-4-yl)-amine

To a solution of N-(1-trityl-1H-imidazol-4-yl)-benzamide (0.36 g, 0.83mmol) in tetrahydrofuran (10 ml) was added portionwise lithium aluminiumhydride (0.16 g, 4.14 mmol). The reaction mixture was stirred at 80° C.for 16 hours, then cooled to room temperature and water added dropwise.The mixture was stirred at room temperature for 20 minutes and thenextracted with ethyl acetate. The organic layer was separated, washedwith water, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (eluant:methanol/dichloromethane 0:100 to 10:90) to yield the title compound asa white solid (0.15 g, 44%); MS (ISP): 416.5 ([M+H]⁺).

c) Benzyl-(1H-imidazol-4-yl)-amine hydrochloride

Benzyl-(1-trityl-1H-imidazol-4-yl)-amine (0.15 g, 0.35 mmol) wasdissolved in a 4 M solution of HCl in dioxane (5 ml). The mixture wasstirred at room temperature for 90 minutes and then concentrated invacuo. The residue was triturated in ether to yield the title compoundas an off-white solid (73 mg, 100%); MS (ISP): 174.4 ([M+H]⁺).

Compounds of examples 1-48 are new. Compounds of examples A-N are known.

Example 49

The ability of the compounds of the present invention to bind to TAAR1was demonstrated in accordance with the test given hereinafter.

Materials and Methods Construction of TAAR Expression Plasmids andStably Transfected Cell Lines

For the construction of expression plasmids, the coding sequences ofhuman, rat and mouse TAAR 1 were amplified from genomic DNA essentiallyas described by Lindemann et al. (2005) Genomics 85, 372-385. The ExpandHigh Fidelity PCR System (Roche Diagnostics) was used with 1.5 mM Mg²⁺and purified PCR products were cloned into pCR2.1-TOPO cloning vector(Invitrogen) following the instructions of the manufacturer. PCRproducts were subcloned into the pIRESneo2 vector (BD Clontech, PaloAlto, Calif.), and expression vectors were sequence verified beforeintroduction in cell lines.

HEK293 cells (ATCC # CRL-1573) were cultured essentially as described inLindemann et al. (2005) Genomics 85, 372-385. For the generation ofstably transfected cell lines, HEK293 cells were transfected with thepIRESneo2 expression plasmids containing the TAAR coding sequences(described above) with Lipofectamine 2000 (Invitrogen) according to theinstructions of the manufacturer, and 24 hours post transfection, theculture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs,Switzerland). After a culture period of about 10 days, clones wereisolated, expanded and tested for responsiveness to trace amines (allcompounds purchased from Sigma) with the cAMP Biotrak Enzyme immunoassay(EIA) System (Amersham) following the non-acetylation EIA procedureprovided by the manufacturer. Monoclonal cell lines which displayed astable EC₅₀ for a culture period of 15 passages were used for allsubsequent studies.

Membrane Preparation and Radioligand Binding

Cells at confluence were rinsed with ice-cold phosphate buffered salinewithout Ca²⁺ and Mg²⁺ containing 10 mM EDTA and pelleted bycentrifugation at 1000 rpm for 5 minutes at 4° C. The pellet was thenwashed twice with ice-cold phosphate buffered saline and the cell pelletwas frozen immediately by immersion in liquid nitrogen and stored untiluse at −80° C. The cell pellet was then suspended in 20 ml HEPES-NaOH(20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron(PT 3000, Kinematica) at 10,000 rpm for 10 seconds. The homogenate wascentrifuged at 48,000×g for 30 minutes at 4° C. and the pelletresuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA(buffer A), and homogenized with a Polytron at 10,000 rpm for 10seconds. The homogenate was then centrifuged at 48,000×g for 30 minutesat 4° C. and the pellet resuspended in 20 ml buffer A, and homogenizedwith a Polytron at 10,000 rpm for 10 seconds. Protein concentration wasdetermined by the method of Pierce (Rockford, Ill.). The homogenate wasthen centrifuged at 48,000×g for 10 minutes at 4° C., resuspended inHEPES-NaOH (20 mM), pH 7.0 including MgCl₂ (10 mM) and CaCl₂ (2 ml)(buffer B) at 200 μg protein per ml and homogenized with a Polytron at10,000 rpm for 10 seconds.

Binding assay was performed at 4° C. in a final volume of 1 ml, and withan incubation time of 30 minutes. The radioligand[³H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline was used at aconcentration equal to the calculated K_(d) value of 60 nM to give atotal binding at around 0.1% of the total added radioligandconcentration, and a specific binding which represented approximately70-80% of the total binding. Non-specific binding was defined as theamount of [³H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline boundin the presence of the appropriate unlabelled ligand (10 μM). Competingligands were tested in a wide range of concentrations (10 μM-30 μM). Thefinal dimethylsulphoxide concentration in the assay was 2%, and it didnot affect radioligand binding. Each experiment was performed induplicate. All incubations were terminated by rapid filtration throughUniFilter-96 plates (Packard Instrument Company) and glass filter GF/C,pre-soaked for at least 2 hours in polyethylenimine 0.3%, and using aFiltermate 96 Cell Harvester (Packard Instrument Company). The tubes andfilters were then washed 3 times with 1 ml aliquots of cold buffer B.Filters were not dried and soaked in Ultima gold (45 μl/well, PackardInstrument Company) and bound radioactivity was counted by a TopCountMicroplate Scintillation Counter (Packard Instrument Company).

The preferred compounds show a Ki value (μM) in mouse on TAAR1 in therange of <0.1 μM as shown in the table below.

Ki (μM) Example mouse Example Ki 1 0.0609 39 0.0684 5 0.0059 42 0.0041 80.0843 46 0.0146 11 0.0025 47 0.0103 12 0.0097 13 0.0106 14 0.0606 160.0172 17 0.0019 20 0.043 35 0.0889 36 0.0227 37 0.0802

Example 50

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. LactoseAnhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. MicrocrystallineCellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add item 5 and mix for three minutes; compress on a suitable press.

Example 52

Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148— 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 12 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add items 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

1. A compound according to formula I,

wherein R is selected from the group consisting of hydrogen, lower alkyland amino; X is selected from the group consisting of —CH₂—, —CH(loweralkoxy)-, —CH(OH)—, and —NH—; Y is selected from the group consisting of—CH₂, —CH(lower alkyl)-, —CH(lower alkoxy)-, —O—, —S—, —S(O)—, —S(O)₂—,—CH(phenyl)- and —C(lower alkyl)₂-; and Ar is selected from the groupconsisting of phenyl, napthtyl and benzofuranyl, said phenyl, mapthyl,or benzofuranyl being unsubstituted or substituted by one or moresubstituents, each substituent being independently selected from thegroup consisting of lower alkyl, lower alkyl substituted by halogen,halogen, lower alkoxy, lower alkoxy substituted by halogen, hydroxy,amino, di-alkylamino, morpholinyl, phenyl, benzyl and O-benzyl; or apharmaceutically-suitable acid-addition salt thereof; with the provisiothat, wherein, when X is —NH—, Y is selected from the group consistingof —CH₂, —CH(lower alkyl)-, —CH(lower alkoxy)-, —CH(phenyl)- or —C(loweralkyl)₂-; and the further proviso that said compound is not5-phenethyl-1H-imidazole, 5-(2-phenyl-propyl)-1H-imidazole,1-(1H-imidazol-4-yl)-2-phenyl-ethanol,5-(2,2-diphenyl-ethyl)-1H-imidazole, 4-(2-m-tolyl-ethyl)-1H-imidazole,4-[2-(2,6-dimethyl-phenyl)-ethyl]-1H-imidazole,4-(biphenyl-2-yloxymethyl)-1H-imidazole,5-(2-methyl-2-phenyl-propyl)-1H-imidazole,4-(2-chloro-phenoxymethyl)-1H-imidazole,4-(2-fluoro-phenoxymethyl)-1H-imidazole,4-o-tolyloxymethyl-1H-imidazole,4-(3-chloro-phenoxymethyl)-1H-imidazole,4-(2,6-dimethyl-phenoxymethyl)-1H-imidazole, or5-methyl-4-phenylsulfanylmethyl-1H-imidazole.
 2. A compound according toclaim 1, wherein X and Y are both —CH₂—.
 3. A compound according toclaim 2, selected from the group consisting of:4-[2-(2-chloro-phenyl)-ethyl]-1H-imidazole;4-[2-(2-methoxy-phenyl)-ethyl]-1H-imidazole;4-[2-(3-chloro-phenyl)-ethyl]-1H-imidazole;4-[2-(3-fluoro-phenyl)-ethyl]-1H-imidazole;4-[2-(3-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;4-[2-(3-methoxy-phenyl)-ethyl]-1H-imidazole;4-[2-(4-chloro-phenyl)-ethyl]-1H-imidazole;4-[2-(3,5-dichloro-phenyl)-ethyl]-1H-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 4. A compoundaccording to claim 1, wherein X is —CH₂— and Y is —CH(lower alkyl).
 5. Acompound according to claim 4, selected from the group consisting of:4-(2-phenyl-butyl)-1H-imidazole; and pharmaceutically-suitableacid-addition salts thereof.
 6. A compound according to claim 1, whereinX is —CH₂— and Y is —O—.
 7. A compound according to claim 6, selectedfrom the group consisting of:4-(2,3-dichloro-phenoxymethyl)-1H-imidazole;4-(2,3-difluoro-phenoxymethyl)-1H-imidazole;4-(3,4-dichloro-phenoxymethyl)-1H-imidazole;4-(4-chloro-3-fluoro-phenoxymethyl)-1H-imidazole;5-(benzofuran-6-yloxymethyl)-1H-imidazole; and pharmaceutically-suitableacid-addition salts thereof.
 8. A compound according to claim 1, whereinX is —CH₂— and Y is —S—.
 9. A compound according to claim 8, selectedfrom the group consisting of:5-(2,3-dichloro-phenylsulfanylmethyl)-1-imidazole;4-(4-chloro-phenylsulfanylmethyl)-5-methyl-1H-imidazole;4-(naphthalen-2-ylsulfanylmethyl)-1H-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 10. A compositioncomprising a compound according to claim 1 and a therapeutically-inertcarrier.
 11. A process for the preparation of a compound of formula I,

comprising deprotecting a compound according to formula II,

wherein, in the above formulas, R is selected from the group consistingof hydrogen, lower alkyl and amino; X is selected from the groupconsisting of —CH₂—, —CH(lower alkoxy)-, —CH(OH)—, and —NH—; Y isselected from the group consisting of —CH₂, —CH(lower alkyl)-, —CH(loweralkoxy)-, —O—, —S—, —S(O)—, —S(O)₂—, —CH(phenyl)- and —C(lower alkyl)₂-;and Ar is selected from the group consisting of phenyl, napthtyl andbenzofuranyl, said phenyl, mapthyl, or benzofuranyl being unsubstitutedor substituted by one or more substituents, each substituent beingindependently selected from the group consisting of lower alkyl, loweralkyl substituted by halogen, halogen, lower alkoxy, lower alkoxysubstituted by halogen, hydroxy, amino, di-alkylamino, morpholinyl,phenyl, benzyl and O-benzyl; with the provisio that, wherein, when X is—NH—, Y is selected from the group consisting of —CH₂, —CH(loweralkyl)-, —CH(lower alkoxy)-, —CH(phenyl)- or —C(lower alkyl)₂-.
 12. Acompound according to claim 2 wherein said compound is selected from thegroup consisting of: 4-[2-(2-ethyl-phenyl)-ethyl]-1H-imidazole;4-[2-(2-trifluoromethyl-phenyl)-ethyl]-1H-imidazole;{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-dimethyl-amine;4-{2-[2-(1H-imidazol-4-yl)-ethyl]-phenyl}-morpholine;4-[2-(3-trifluoromethoxy-phenyl)-ethyl]-1H-imidazole;2-methyl-5-phenethyl-1H-imidazole; 5-phenethyl-1H-imidazol-2-ylamine;and pharmaceutically-suitable acid-addition salts thereof.
 13. Acompound according to claim 3 wherein said compound is selected from thegroup consisting of: 4-(3-methyl-2-phenyl-butyl)-1H-imidazole;4-(3,3-dimethyl-2-phenyl-butyl)-1H-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 14. A compoundaccording to claim 6 wherein said compound is selected from the groupconsisting of: 4-(2-Ethyl-phenoxymethyl)-1H-imidazole;4-(2-Isopropyl-phenoxymethyl)-1H-imidazole;4-(2-Trifluoromethyl-phenoxymethyl)-1H-imidazole;4-(2-Benzyl-phenoxymethyl)-1H-imidazole;4-(2-Methoxy-phenoxymethyl)-1H-imidazole;4-(2-Isopropoxy-phenoxymethyl)-1H-imidazole;4-(2-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;4-(2-Benzyloxy-phenoxymethyl)-1H-imidazole;2-(1H-Imidazol-4-ylmethoxy)-phenol;4-(3-Trifluoromethyl-phenoxymethyl)-1H-imidazole;4-(3-Trifluoromethoxy-phenoxymethyl)-1H-imidazole;[3-(1H-Imidazol-4-ylmethoxy)-phenyl]-dimethyl-amine;4-[-(1H-Imidazol-4-ylmethoxy)-phenyl]-morpholine;4-(2,6-Diethyl-phenoxymethyl)-1H-imidazole;4-(3,4-Difluoro-phenoxymethyl)-1H-imidazole;4-(3-Chloro-5-fluoro-phenoxymethyl)-1H-imidazole;5-(4-Bromo-2,6-dimethyl-phenoxymethyl)-1H-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 15. A compoundaccording to claim 1 wherein X is —CH₂— and Y is —S(O)—, said compoundselected from the group consisting of:4-benzenesulfinylmethyl-5-methyl-1H-imidazole;5-(2,3-dichloro-benzenesulfinylmethyl)-1-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 16. A compoundaccording to claim 1 wherein X is —CH₂— and Y is —S(O)₂—, said compoundselected from the group consisting of:5-(2,3-dichloro-benzenesulfonylmethyl)-1-imidazole; andpharmaceutically-suitable acid-addition salts thereof.
 17. A compoundaccording to claim 1 wherein X is —NH— and Y is —CH₂—, said compoundselected from the group consisting of: Benzyl-(1H-imidazol-4-yl)-amine;and pharmaceutically-suitable acid-addition salts thereof.
 18. Acompound according to claim 1 wherein X is —CH(lower alkoxy)- and Y is—CH₂—, said compound selected from the group consisting of:4-(1-methoxy-2-phenyl-ethyl)-1H-imidazole; and pharmaceutically-suitableacid-addition salts thereof.